Chen Zhe, Ma Xiao, Zhu Yun, Zhao Yanling, Wang Jiabo, Li Ruisheng, Chen Chang, Wei Shizhang, Jiao Wenjuan, Zhang Yaming, Li Jianyu, Wang Lifu, Wang Ruilin, Liu Honghong, Shen Honghui, Xiao Xiaohe
Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Department of Pharmacy, 302 Hospital of People's Liberation Army, Beijing, 100039, China.
Phytother Res. 2015 Nov;29(11):1768-75. doi: 10.1002/ptr.5431. Epub 2015 Aug 13.
Cholestasis causes hepatic accumulation of bile acids leading to liver injury, fibrosis and liver failure. Paeoniflorin, the major active compound isolated from the roots of Paeonia lactiflora pall and Paeonia veitchii Lynch, is extensively used for liver diseases treatment in China. However, the mechanism of paeoniflorin's hepatoprotective effect on cholestasis has not been investigated yet. In this study, we administered paeoniflorin to rats for 3 days prior to alpha-naphthylisothiocyanate (ANIT) administration for once, then went on administering paeoniflorin to rats for 3 days. The data demonstrated that paeoniflorin significantly prevented ANIT-induced change in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphates (ALP), serum total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA) and gamma-glutamyl transpeptidase (γ-GT). Histology examination revealed that paeoniflorin treatment rats relieved more liver injury and bile duct proliferation than ANIT-administered rats. Moreover, our data indicated that paeoniflorin could restore glutathione (GSH) and its related synthase glutamate-cysteine ligase catalytic subunit (GCLc) and glutamate-cysteine ligase modifier subunit (GCLm) in ANIT-treated group. In addition, the RNA and protein expression of Akt and nuclear factor-E2-related factor-2 (Nrf2) were also activated by paeoniflorin in ANIT-induced rats. These findings indicated that paeoniflorin protected ANIT-induced cholestasis and increased GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. Therefore, paeoniflorin might be a potential therapeutic agent for cholestasis.
胆汁淤积会导致胆汁酸在肝脏中蓄积，进而引发肝损伤、肝纤维化和肝衰竭。芍药苷是从芍药根和川赤芍根中分离出的主要活性化合物，在中国被广泛用于治疗肝脏疾病。然而，芍药苷对胆汁淤积的肝保护作用机制尚未得到研究。在本研究中，我们在给予大鼠一次异硫氰酸α-萘酯（ANIT）之前3天给予芍药苷，然后继续给大鼠服用芍药苷3天。数据表明，芍药苷显著预防了ANIT诱导的血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）、血清总胆红素（TBIL）、直接胆红素（DBIL）、总胆汁酸（TBA）和γ-谷氨酰转肽酶（γ-GT）的变化。组织学检查显示，与给予ANIT的大鼠相比，用芍药苷治疗的大鼠肝损伤和胆管增生减轻更多。此外，我们的数据表明，芍药苷可以恢复ANIT治疗组中的谷胱甘肽（GSH）及其相关合成酶谷氨酸-半胱氨酸连接酶催化亚基（GCLc）和谷氨酸-半胱氨酸连接酶调节亚基（GCLm）。此外，在ANIT诱导的大鼠中，芍药苷还激活了Akt和核因子E2相关因子2（Nrf2）的RNA和蛋白质表达。这些发现表明，芍药苷通过PI3K/Akt依赖性途径激活Nrf2，从而保护ANIT诱导的胆汁淤积并增加GSH合成。因此，芍药苷可能是治疗胆汁淤积的潜在治疗药物。
